Source-dependent temporal toxicity and transcriptomic remodeling by urban ultrafine particles: Megacity - suburban comparison in aging olfactory-brain interface

Ultrafine particles (UFPs), an integral component of air pollution generated through dynamic processes, possess high surface reactivity and heterogeneous chemistry that drives toxicity. UFPs toxicity is associated with oxidative stress and inflammation at the olfactory-brain interface, which are also common in age-related diseases of the brain. However, how UFPs composition shapes time-resolved cellular injury and adaptation in aged individuals remains unclear. Cells of the olfactory mucosa (OM), which directly interface with inhaled air and provide access to the brain, offer a relevant model to assess these effects. This study investigates source-specific and time-dependent effects of UFPs on primary human OM cells, focusing on the interplay between particle composition, exposure duration, and age-related susceptibility to UFPs. OM cells from aged female donors were exposed invitro to well-characterized UFPs collected from a megacity (Nanjing, China) and a Nordic urban area (Kuopio, Finland). Transcriptional responses were profiled at 4, 12, 24, and 72 h, alongside assays for cytotoxicity, DNA damage, and cell-cycle dynamics. Interaction modeling identified 2614 genes with divergent temporal trajectories between sources. Nanjing metals and polycyclic aromatic hydrocarbons rich UFPs produced sustained oxidative stress, DNA damage, early G0/G1 checkpoint activation, and a senescence-linked transcriptional program (p53/p21 axis). While Kuopio mineral−/biomass- influenced UFPs elicited a milder viability loss, S/G2 enrichment, and a compensatory proliferative transcriptomic signature after 12 h exposure. Overall, UFP-induced toxicity in OM cells is both source- and time-dependent. UFPs chemical properties dictated the pace and nature of cellular response and adaptation at the olfactory interface in OM cells derived from aged individuals, underscoring the need for composition-aware air-pollution risk assessment in aging populations.